Deprecated: The each() function is deprecated. This message will be suppressed on further calls in /home/zhenxiangba/zhenxiangba.com/public_html/phproxy-improved-master/index.php on line 456
US8568779B2 - Method for producing coenzyme Q10 particle - Google Patents
[go: Go Back, main page]

US8568779B2 - Method for producing coenzyme Q10 particle - Google Patents

Method for producing coenzyme Q10 particle Download PDF

Info

Publication number
US8568779B2
US8568779B2 US12/522,792 US52279208A US8568779B2 US 8568779 B2 US8568779 B2 US 8568779B2 US 52279208 A US52279208 A US 52279208A US 8568779 B2 US8568779 B2 US 8568779B2
Authority
US
United States
Prior art keywords
coenzyme
particles
production method
poor solvent
fatty acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active, expires
Application number
US12/522,792
Other languages
English (en)
Other versions
US20100004473A1 (en
Inventor
Kento Kanaya
Shiro Kitamura
Takahiro Ueda
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kaneka Corp
Original Assignee
Kaneka Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kaneka Corp filed Critical Kaneka Corp
Assigned to KANEKA CORPORATION reassignment KANEKA CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KANAYA, KENTO, KITAMURA, SHIRO, UEDA, TAKAHIRO
Publication of US20100004473A1 publication Critical patent/US20100004473A1/en
Assigned to KANEKA CORPORATION reassignment KANEKA CORPORATION CHANGE OF ADDRESS Assignors: KANEKA CORPORATION
Application granted granted Critical
Publication of US8568779B2 publication Critical patent/US8568779B2/en
Active legal-status Critical Current
Adjusted expiration legal-status Critical

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2250/00—Food ingredients
    • A23V2250/30—Other Organic compounds
    • A23V2250/314—Ubiquinone, coenzyme Qn
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C46/00—Preparation of quinones
    • C07C46/10—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C50/00—Quinones
    • C07C50/26—Quinones containing groups having oxygen atoms singly bound to carbon atoms
    • C07C50/28—Quinones containing groups having oxygen atoms singly bound to carbon atoms with monocyclic quinoid structure
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K15/00—Anti-oxidant compositions; Compositions inhibiting chemical change
    • C09K15/04—Anti-oxidant compositions; Compositions inhibiting chemical change containing organic compounds
    • C09K15/06—Anti-oxidant compositions; Compositions inhibiting chemical change containing organic compounds containing oxygen
    • C09K15/08—Anti-oxidant compositions; Compositions inhibiting chemical change containing organic compounds containing oxygen containing a phenol or quinone moiety

Definitions

  • Coenzyme Q 10 is a compound useful as a superior food, food with nutrient function claims, food for specified health uses, nutritional supplement, nutritional product, animal drug, beverage, feed, pet food, cosmetic, pharmaceutical, therapeutic drug, prophylactic drug or the like.
  • Coenzyme Q is an essential component widely distributed in living organisms from bacterium to mammal, and is known as a constituent component of an electron transport system of mitochondria in a living cell. Coenzyme Q includes an oxidized type and a reduced type. It repeats oxidization and reduction in mitochondria, thereby functioning as a transduction component in the electron transport system, and reduced coenzyme Q is known to have an antioxidant action.
  • coenzyme Q 10 which is a coenzyme Q having a side chain with 10 repeat units, is the main component, and generally, about 40-90% thereof is a reduced type in the living body.
  • the physiological action of coenzyme Q 10 includes activation of energy production by mitochondria-activating action, activation of cardiac function, cellular membrane stabilization effect, cell protection effect by antioxidant action and the like.
  • oxidized coenzyme Q 10 is used as a health food in Europe and the United States and as a drug for congestive heart failure in Japan. In recent years, it is also used as a food with nutrient function claims in Japan. Particularly, products of oxidized coenzyme Q 10 contained in a soft capsule have been mainly used in the fields of health food and food with nutrient function claims. On the other hand, reduced coenzyme Q 10 has not attracted much attention heretofore. In recent years, however, it has been reported to be more effective than oxidized coenzyme Q 10 in various applications. For example, a composition containing reduced coenzyme Q 10 has been reported to be superior to conventional oxidized coenzyme Q 10 alone in the oral absorbability (patent document 1).
  • the bulk powders of coenzyme Q 10 which may be reduced coenzyme Q 10 , oxidized coenzyme Q 10 or a mixture of them, can be obtained, for example, by producing a crude purification product of coenzyme Q 10 by a method such as synthesis, fermentation, extraction from naturally occurring substances and the like, concentrating a coenzyme Q 10 fraction in an outflow fluid by chromatography, and crystallizing the concentrate by crystal precipitation.
  • the thus-obtained bulk powder of coenzyme Q 10 takes the form of an ultrafine plate crystal or capillary crystal, which may be stirred up as dust during handling of the powder or stick to a solid surface, causing difficulty in brushing off the entire amount of the powder from a packaging material such as a bag and the like since it attaches thereto.
  • the powder often agglomerates to form a mass during preservation, thus rendering the handling very difficult, and is known to show markedly poor powder flowability characteristics.
  • the powder attaches to bulk powder containers and formulation apparatuses during tableting or capsule filling, thus causing problems in productivity and operability since coenzyme Q 10 preparations cannot be formulated smoothly, and the like.
  • a granulation method for reduced coenzyme Q 10 a method including crystallizing an oily substance of reduced coenzyme Q 10 in water to give reduced coenzyme Q 10 (patent document 5) and a method including adding a liquid phase of high concentration of reduced coenzyme Q 10 to a poor solvent for granulation (patent document 6) are known. According to these granulation methods, control of the resulting particle size is difficult, and an additional facility such as a tank for preparation of a high concentration liquid phase, a pump for delivery of liquid and the like is necessary.
  • the problem of the present invention is to provide a production method capable of efficient industrial production of coenzyme Q 10 particles having a high content and superior powder flowability characteristics, by simple facility and convenient operations.
  • the present inventors have conducted intensive studies in an attempt to solve the aforementioned problem and found that coenzyme Q 10 particles having a high content and superior powder flowability characteristics can be produced efficiently by an industrially possible method by stirring and dispersing coenzyme Q 10 into the form of oil droplets in a particular solvent and solidifying them by cooling with stirring, which resulted in the completion of the present invention. Accordingly, the present invention provides the following.
  • the particles of coenzyme Q 10 obtained by the present invention are not stirred up as dust during handling, are easily brushed off from a packaging material such as a bag and the like, are easily blended with other substances, have a uniform particle size and are superior in powder flowability characteristics, do not easily attach to bulk powder containers and preparation apparatuses, and are superior in apparatus filling property.
  • the production method of the present invention can be performed using simple facility and by convenient operations, enables granulation even without using a dispersing agent, an excipient and the like, and enables production of particles having a high coenzyme Q 10 content.
  • coenzyme Q 10 particles having a high content and superior in powder property can be efficiently produced in large amounts at a low production cost.
  • FIG. 1 is an SEM photograph of oxidized coenzyme Q 10 particles obtained in Example 1.
  • FIG. 2 is an SEM photograph of oxidized coenzyme Q 10 particles obtained in Example 2.
  • FIG. 3 is an SEM photograph of oxidized coenzyme Q 10 bulk powder of Comparative Example 1.
  • FIG. 4 is an SEM photograph of oxidized coenzyme Q 10 particles obtained in Comparative Example 3.
  • the production method of the present invention produces coenzyme Q 10 particles by mixing coenzyme Q 10 and a poor solvent by stirring at a temperature not less than the melting point of coenzyme Q 10 , dispersing coenzyme Q 10 into the form of oil droplets, and cooling them to a solidification temperature of coenzyme Q 10 or below while stirring the dispersion, and the method is characterized by the use of a particular poor solvent to produce a coenzyme Q 10 oil droplet dispersion.
  • Coenzyme Q 10 is an essential component widely distributed in living organisms and, as mentioned above, includes oxidized type and reduced type.
  • any of the oxidized coenzyme Q 10 and reduced coenzyme Q 10 can be used as the coenzyme Q 10 to obtain particles superior in powder flowability characteristics.
  • coenzyme Q 10 may be a mixture of oxidized coenzyme Q 10 and reduced coenzyme Q 10 .
  • the production method of the present invention can be applied to any of the forms mentioned above.
  • the method is generally preferably applied as coenzyme Q 10 to reduced coenzyme Q 10 or a mixture of oxidized coenzyme Q 10 and reduced coenzyme Q 10 .
  • the ratio of reduced coenzyme Q 10 in coenzyme Q 10 is preferably not less than 20 wt %, more preferably not less than 40 wt %, more preferably not less than 50 wt %, most preferably not less than 60 wt %, particularly preferably not less than 80 wt %, specially not less than about 90 wt %, essentially not less than about 96 wt %.
  • the upper limit of the content of the reduced coenzyme Q 10 is not particularly limited, it is generally not more than about 99.9 wt % in the case of a mixture. Needless to say, reduced coenzyme Q 10 can be used alone.
  • Coenzyme Q 10 to be used for the production method of the present invention may be commercially available or produced and purified by a known production method.
  • reduced coenzyme Q 10 or a mixture of oxidized coenzyme Q 10 and reduced coenzyme Q 10 is used as coenzyme Q 10
  • reduced coenzyme Q 10 may be obtained by reducing an oily substance of oxidized coenzyme Q 10 in water.
  • the usable reducing agent include metal hydride compound, iron (metal or iron as salt), zinc (zinc as metal), hydrosulfurous acids, ascorbic acids and the like.
  • the above-mentioned metal hydride compound is not particularly limited, examples thereof include sodium borohydride, lithium aluminum hydride and the like.
  • the amount of the above-mentioned metal hydride compound to be used varies depending on the kind of the metal hydride compound and cannot be uniformly defined. However, it is generally preferably theoretical hydrogen equivalent—3-fold amount thereof.
  • Reduction using the above-mentioned iron or zinc is normally performed using an acid.
  • the acid to be used is not particularly limited, it is, for example, fatty acid such as acetic acid and the like, sulfonic acid such as methanesulfonic acid and the like, inorganic acid such as hydrochloric acid, sulfuric acid and the like, and the like. It is preferably an inorganic acid, more preferably sulfuric acid.
  • the amount of iron to be used is not particularly limited, for example, the reduction can be performed using preferably not less than about 1 ⁇ 5 weight relative to the charge weight of oxidized coenzyme Q 10 .
  • the upper limit is not particularly limited, it is not more than about 2-fold weight from the economic aspect and the like.
  • Iron can be used not only in the form of metal iron but also salt such as iron(II) sulfate and the like. While the amount of zinc to be used is not particularly limited, the reduction can be preferably performed using not less than about 1/10 weight relative to the charge weight of oxidized coenzyme Q 10 . While the upper limit is not particularly limited, it is not more than about 2-fold weight from the economic aspect and the like.
  • hydrosulfurous acids are not particularly limited, hydrosulfite is generally used.
  • the hydrosulfite is not particularly limited, alkali metal salt, alkaline earth metal salt, ammonium salt and the like are preferable, alkali metal salts such as lithium salt, sodium salt, potassium salt and the like are more preferable, and sodium salt is most preferable.
  • the amount of the above-mentioned hydrosulfurous acids to be used is not particularly limited, it is normally not less than about 1 ⁇ 5 weight, preferably not less than about 2 ⁇ 5 weight, more preferably not less than about 3 ⁇ 5 weight, relative to the charge weight of oxidized coenzyme Q 10 .
  • a large amount thereof does not cause particular inconvenience but, from the economical aspects, not more than about twice the weight, preferably not more than equivalent weight, is generally employed. Therefore, the reduction can be preferably performed using about 2 ⁇ 5 weight—about equivalent weight thereof.
  • the reduction using the above-mentioned hydrosulfurous acids is performed generally pH 7 or below, preferably pH 3-7, more preferably pH 3-6, from the aspects of yield and the like.
  • the above-mentioned pH can be adjusted using an acid (e.g., inorganic acid such as hydrochloric acid, sulfuric acid and the like) or a base (e.g., alkali metal hydroxide such as sodium hydroxide and the like).
  • ascorbic acids are not particularly limited. Examples thereof include not only ascorbic acid but also those analogous to ascorbic acid such as rhamno-ascorbic acid, arabo-ascorbic acid, gluco-ascorbic acid, fuco-ascorbic acid, glucohepto-ascorbic acid, xylo-ascorbic acid, galacto-ascorbic acid, gulo-ascorbic acid, allo-ascorbic acid, erythro-ascorbic acid, 6-deoxyascorbic acid and the like.
  • an ester or salt thereof can also be used. They may also be L form, D form or racemate.
  • L-ascorbic acid examples include L-ascorbic acid, L-ascorbic acid palmitate, L-ascorbic stearate, L-sodium ascorbate, L-calcium ascorbate, D-arabo-ascorbic acid and the like. While any of the above-mentioned ascorbic acids can be preferably used, in consideration of easy separation from the resulting reduced coenzyme Q 10 and the like, water-soluble ones from among the above-mentioned ascorbic acids are particularly preferably used. Most preferred from the aspects of easy availability, cost and the like are L-ascorbic acid, D-arabo-ascorbic acid, L-sodium ascorbate and the like.
  • the amount of the above-mentioned ascorbic acids to be used is not particularly limited, and only needs to be an effective amount capable of converting oxidized coenzyme Q 10 to reduced coenzyme Q 10 .
  • it is normally not less than is 1-fold molar amount, preferably not less than 1.2-fold molar amount, relative to oxidized coenzyme Q 10 .
  • the upper limit is not particularly limited, in consideration of the economic aspect, it is normally 10-fold molar amount, preferably 5-fold molar amount, more preferably 3-fold molar amount.
  • hydrosulfurous acids specifically hydrosulfite
  • ascorbic acids are particularly more preferable
  • ascorbic acids are particularly preferable, from the aspects of reducing ability, yield and quality.
  • the resulting oily substance containing reduced coenzyme Q 10 is used as it is and dispersed and solidified in a poor solvent to give particles.
  • an oily substance of reduced coenzyme Q 10 can also be collected by partitioning, extraction and the like, repeatedly washed with, for example, water, brine etc. to remove contaminants, and put to use.
  • the poor solvent to be used in the present invention needs to disperse coenzyme Q 10 into the form of oil droplets at not less than the melting point thereof, and maintain its dispersion state well.
  • an aqueous solution containing an organic solvent and/or a surfactant having an HLB of not less than 6 is used in the present invention.
  • one capable of completely dissolving coenzyme Q 10 at not less than the melting point thereof, namely, a good solvent cannot afford a coenzyme Q 10 dispersion and does not fall under a poor solvent in the present invention.
  • the organic solvent that can be contained in an aqueous solution to be used as a poor solvent is not particularly limited.
  • a water-soluble organic solvent is preferable.
  • at least one kind of organic solvent from ketones, alcohols, nitrites and ethers is more preferable.
  • ketones are not particularly limited, normally, one having a carbon number of 3-6 is preferably used.
  • Specific examples include acetone, methylethyl ketone, methylbutylketone, methylisobutylketone and the like. Among these, acetone, methylethyl ketone and the like are preferable, and acetone is most preferable.
  • the above-mentioned alcohols may be cyclic or acyclic, and saturated or unsaturated, and are not particularly limited. Generally, saturated one is preferably used. Particularly, monovalent alcohol having a carbon number of 1-5, divalent alcohol having a carbon number of 2-5 and trivalent alcohol having a carbon number of 3 are preferable.
  • monohydric alcohol examples include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutyl alcohol, 1-pentanol, 2-pentanol, 3-pentanol and the like.
  • divalent alcohol examples include 1,2-ethanediol, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, 2,3-butanediol, 1,5-pentanediol and the like.
  • trivalent alcohol glycerol and the like can be used as the trivalent alcohol.
  • nitriles may be cyclic or acyclic, and saturated or unsaturated, and are not particularly limited. Generally, saturated one is preferably used. Normally, one having a carbon number of 2-8, particularly 2-6, especially 2-4, is preferably used. Specific examples thereof include acetonitrile, propionitrile, succinonitrile, butyronitrile, isobutyronitrile and the like.
  • ethers may be cyclic or acyclic, and saturated or unsaturated, and are not particularly limited. Generally, saturated one is preferably used. Specific examples thereof include diethyl ether, methyl tert-butylether, anisole, dioxane, tetrahydrofuran and the like.
  • alcohol is preferably used from among the above-mentioned organic solvents. More preferably, alcohol having a carbon number of 1 to 5 is used, and most preferably, ethanol is used.
  • the concentration of the organic solvent in the poor solvent is not particularly limited, and can be appropriately selected from the range of generally 1-99 v/v % according to the dispersion state of coenzyme Q 10 oil droplets.
  • the concentration thereof in a poor solvent is not particularly limited. It is preferably 10-70 v/v %, more preferably 10-50 v/v %.
  • the concentration is more preferably 30-50 v/v %.
  • Oxidized coenzyme Q 10 and reduced coenzyme Q 10 show somewhat different compatibility with ethanol.
  • reduced coenzyme Q 10 a good oil droplet dispersion can be obtained even when an aqueous solution having a low ethanol content is used, as compared to oxidized coenzyme Q 10 .
  • oxidized coenzyme Q 10 alone, or coenzyme Q 10 having a high oxidized coenzyme Q 10 ratio is used as coenzyme Q 10 in the production method of the present invention, 30-50 v/v % aqueous ethanol solution (aqueous solution containing ethanol at the concentration) is optimally used as a poor solvent.
  • the surfactant that can be contained in an aqueous solution to be used as a poor solvent any can be used as long as it has an HLB of not less than 6.
  • One usable for food or pharmaceutical products is preferable.
  • examples thereof include partial glyceride of fatty acid, phospholipid, saponin, sucrose fatty acid ester, sorbitan fatty acid ester, sorbitan polyoxyethylene fatty acid ester, polyglycerin fatty acid ester, condensed ricinoleic acid polyglyceride and the like, which have an HLB of not less than 6.
  • partial glyceride of fatty acid, sucrose fatty acid ester, sorbitan polyoxyethylene fatty acid ester and polyglycerin fatty acid ester are more preferable.
  • Examples of the above-mentioned partial glyceride of fatty acid include monoglycerol fatty acid esters such as monoglycerol monocaprylate, monoglycerol monocaprate, monoglycerol dicaprylate, monoglycerol dicaprate, monoglycerol dilaurate, monoglycerol dimyristate, monoglycerol distearate, monoglycerol dioleate, monoglycerol dierucate, monoglycerol dibehenate and the like, fatty acid and organic acid esters of monoglycerol such as caprylic acid and succinic acid ester of monoglycerol, stearic acid and citric acid ester of monoglycerol, stearic acid and acetic acid ester of monoglycerol, stearic acid and succinic acid ester of monoglycerol, stearic acid and lactic acid ester of monoglycerol, stearic acid and diacetyltar
  • Examples of the above-mentioned phospholipid include soybean lecithin, egg-yolk lecithin, enzyme decomposition phospholipids thereof and the like.
  • saponins examples include sophora saponin, quillaja saponin, soybean saponin, yucca saponin and the like.
  • sucrose fatty acid ester examples include sucrose wherein one or more of the hydroxyl groups are esterified with fatty acid each having a carbon number of 6-22, such as sucrose laurate, sucrose myristate, sucrose palmitate, sucrose stearate, sucrose oleate, sucrose erucate, sucrose behenate, and the like.
  • sorbitan fatty acid ester examples include sorbitan wherein one or more of the hydroxyl groups are esterified with fatty acid each having a carbon number of 6-18, such as sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate and the like.
  • sorbitan polyoxyethylene fatty acid ester examples include sorbitan polyoxyethylene monopalmitate, sorbitan polyoxyethylene monostearate, sorbitan polyoxyethylene monooleate, sorbitan polyoxyethylene tristearate, sorbitan polyoxyethylene trioleate and the like.
  • polyglycerin fatty acid ester examples include polyglycerol containing polyglycerol having a degree of polymerization of 2 to 10 as a main component, and polyglycerol wherein one or more of the hydroxyl groups are esterified with fatty acid each having a carbon number of 6-22.
  • Examples of the above-mentioned condensed ricinoleic acid polyglyceride include one containing polyglycerol having an average degree of polymerization of 2-10, and one containing polyricinoleic acid having an average condensation degree (average number of condensed ricinoleic acid) of 2-4.
  • tetraglycerol condensed ricinoleic acid ester, pentaglycerol condensed ricinoleic acid ester, hexaglycerol condensed ricinoleic acid ester and the like can be mentioned.
  • the surfactants shown here can also be used in a combination of two or more kinds thereof.
  • HLB is more preferably not less than 8, still more preferably not less than 10, particularly not less than 12.
  • the concentration of the surfactant in a poor solvent is not particularly limited. In consideration of easy particle formation, it is generally not less than about 0.001 wt %, preferably not less than about 0.005 wt %, more preferably not less than about 0.01 wt %.
  • the concentration of the surfactant in a poor solvent is high, the upper limit thereof is normally not more than about 5 wt %, preferably not more than about 1 wt %, more preferably not more than about 0.5 wt %, more preferably not more than about 0.1 wt %, from the economical aspect as well as the possibility of the obtained coenzyme Q 10 particles becoming too ultrafine.
  • the poor solvent to be used in the production method of the present invention only needs to be an aqueous solution containing either or both of an organic solvent or a surfactant having an HLB of not less than 6.
  • an aqueous solution containing at least an organic solvent namely, an aqueous solution containing at least an organic solvent alone, or both an organic solvent and a surfactant having an HLB of not less than 6 as a poor solvent is more preferable.
  • a preferable kind and amount of use thereof may be any of the above-mentioned examples. It is preferable to preferentially employ specific preferable examples and preferable amount of use of the organic solvent.
  • a poor solvent may further contain a slight amount of a water-soluble dispersing agent.
  • a water-soluble dispersing agent that can be used in the production method of the present invention is not particularly limited, gum arabic, gelatin, agar, starches, pectin, carageenan, casein, alginic acids, soybean polysaccharides, pullulan, curdlan, celluloses, xanthan gum, polyvinyl alcohol, as well as surfactants having an HLB of less than 6 and the like can be used.
  • starches examples include water-soluble starch, cyclodextrin, cluster dextrin, indigestible dextrin and the like.
  • alginic acids examples include alginic acid, sodium alginate, potassium alginate and the like.
  • soybean polysaccharides are polysaccharides extracted from soybean, which are water-soluble dietary fibers.
  • celluloses examples include crystalline cellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, methylcellulose and the like.
  • glycerol fatty acid esters e.g., monoglycerol fatty acid organic acid ester, polyglycerin fatty acid ester etc.: specifically, stearic acid and citric acid ester of monoglycerol, stearic acid and acetic acid ester of monoglycerol, stearic acid and succinic acid ester of monoglycerol, caprylic acid and succinic acid ester of monoglycerol, stearic acid and lactic acid ester of monoglycerol, stearic acid and diacetyltartaric acid ester of monoglycerol, triglycerol monolaurate, triglycerol monomyristate, triglycerol monooleate, triglycerol monostearate, pentaglycerol monomyristate, pentaglycerol trimyristate, pentaglycerol monoo
  • the concentration of the water-soluble dispersing agent contained in a poor solvent is not particularly limited, the dispersing agent is preferably contained such that the concentration becomes 0.001-5 wt %, more preferably 0.01-1 wt %.
  • the charge concentration of coenzyme Q 10 in a poor solvent in the production method of in the present invention is not particularly limited, a higher charge concentration of coenzyme Q 10 in a poor solvent is preferable from the aspect of productivity.
  • it is preferably not less than 10 g/L, particularly not less than 50 g/L.
  • the charge concentration of coenzyme Q 10 in a poor solvent is not less than 200 g/L, control of particle size becomes difficult and particles having high uniformity and high sphericity cannot be obtained easily.
  • the charge concentration is preferably not more than the indicated level.
  • an oil component such as fats and oils, waxes, fatty acids, fatty acid ester derivatives and the like may also be concurrently contained to meet various objects.
  • the oil component can be contained in the obtained coenzyme Q 10 solid particles, and the temperature at which coenzyme Q 10 particles are dissolved, state of particle surface and the like can be conveniently changed variously.
  • fats and oils are not particularly limited, for example, natural fats and oils from animals and plants, synthetic fats and oils and processed fats and oils may be used. More preferably, one acceptable for use for foods, cosmetics or pharmaceutical products can be used.
  • plant fats and oils examples include coconut oil, palm oil, palm kernel oil, linseed oil, camellia oil, brown rice germ oil, rapeseed oil, rice oil, peanut oil, corn oil, wheat germ oil, soybean oil, perilla oil, cottonseed oil, sunflower seed oil, kapok oil, evening primrose oil, shea butter, sal butter, cacao butter, sesame oil, safflower oil, olive oil, jojoba oil, tea oil, Japanese nutmeg oil, avocado oil, pumpkin seed oil, walnut oil, grapeseed oil and the like;
  • animal fats and oils include lard, milk fat, fish oil, beef tallow, egg-yolk oil and the like; furthermore, fats and oils processed therefrom by fractionation, hydrogenation or transesterification (e.g., hydrogenated oil).
  • MCT medium-chain fatty acid triglyceride
  • a mixture thereof may be used.
  • Examples of the medium-chain fatty acid triglyceride include triglyceride wherein fatty acid has 6 to 12 carbon atoms, preferably 8 to 12 carbon atoms.
  • fats and oils oil from plant or animal, synthetic fats and oils, processed fats and oils and the like are preferable from the aspects of easy handling property, odor and the like. More preferable specific examples include coconut oil, palm oil, palm kernel oil, canola oil, rice oil, soy bean oil, cottonseed oil, safflower oil, olive oil, MCT and the like.
  • waxes such as beeswax, rhus succedanea fruit wax, candelilla wax, rice bran wax, carnauba wax, snow wax, cotton wax, bayberry wax, ibota wax, whale wax, montan wax, rice bran wax, lanolin, kapok wax, sugarcane wax, jojoba wax, shellac wax and the like.
  • fatty acids and ester derivatives thereof include, but are not limited to, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, behenic acid, linoleic acid, linolenic acid and esters thereof, for example, methyl esters thereof, ethyl esters thereof and the like.
  • the amount of such oil component to be added cannot be unconditionally defined and varies depending on the object, it is normally not more than about 60 wt %, preferably not more than about 40 wt %, more preferably not more than about 20 wt %, more preferably not more than about 10 wt %, of coenzyme Q 10 .
  • an active substance other than coenzyme Q 10 can also be co-present, like the above-mentioned oil component.
  • the above-mentioned active substance other than coenzyme Q 10 is not particularly limited, one acceptable for use for foods, cosmetics or pharmaceutical products is preferable.
  • glutathione, L-cysteine, N-acetylcysteine, ⁇ -lipoic acid, reduced ⁇ -lipoic acid, tocotrienol vitamin E ( ⁇ -tocopherol) and an ester derivative thereof, vitamin C (ascorbic acid) and an ester derivative or salt thereof, erythorbic acid and an ester derivative or salt thereof, vitamin A and an ester derivative thereof, carotenoid, rutin, zeaxanthine, astaxanthin, lycopene, flavonoid, L-carnitine and pharmacologically acceptable salts such as tartrate thereof, fumarate thereof and the like, acetyl-L-carnitine, propionyl-L-carnitine, magnesium, zinc, selenium, manganese, riboflavin, niacinamide
  • the above-mentioned active ingredient is preferably lipophilic since it can be economically contained in the obtained coenzyme Q 10 particles.
  • tocotrienol, vitamin E ( ⁇ -tocopherol) and an ester derivative thereof, ester derivative of vitamin C, ester derivative of erythorbic acid, vitamin A and an ester derivative thereof, carotenoid, rutin, astaxanthin, lycopene, flavonoid, curcuminoid, licorice hydrophobic extract and the like particularly preferably, carotenoid, astaxanthin, vitamin E and an ester derivative thereof, ester derivative of vitamin C, licorice hydrophobic extract and the like are preferable.
  • various components recited here can also be used in a mixture of two or more kinds thereof.
  • the amount of the active substance other than coenzyme Q 10 to be added cannot be unconditionally defined and varies depending on the object, it is normally not more than about 50 wt %, preferably not more than about 30 wt %, more preferably not more than about 10 wt %, of coenzyme Q 10 .
  • coenzyme Q 10 first needs to be dispersed as an oily substance in a poor solvent.
  • the method of charging coenzyme Q 10 and poor solvent is not particularly limited.
  • a method wherein an organic solvent and water are charged at once, coenzyme Q 10 is added and melted to disperse oil droplets a method wherein coenzyme Q 10 is added to a system using water alone as a solvent and melted to give oil droplets, an organic solvent is added dropwise thereto and the like to gradually allow addition by feeding and the like can be employed.
  • an organic solvent and water and coenzyme Q 10 are charged at once, stirred and heated to melt coenzyme Q 10 into oil droplets.
  • the surfactant may be added to and mixed with coenzyme Q 10 in advance and then mixed with water.
  • it may be added to and dissolved in water and then mixed with coenzyme Q 10 , or it may be added after dispersing coenzyme Q 10 as an oily substance in water or added during dispersion.
  • coenzyme Q 10 and water and a surfactant may be charged at once and the mixture may be heated and mixed.
  • the pH of the poor solvent in which coenzyme Q 10 oily substance is dispersed is not particularly limited.
  • an acidic condition of less than pH 7 is preferably employed by the addition of acid and the like, to protect from oxidation.
  • a temperature not less than a temperature at which coenzyme Q 10 is melted i.e., melting point of coenzyme Q 10 (about 48° C.)
  • melting point of coenzyme Q 10 about 48° C.
  • a mixture of coenzyme Q 10 and a poor solvent is preferably stirred at 50° C.-80° C., more preferably 55° C.-60° C.
  • coenzyme Q 10 can be obtained in the form of oil droplets even at a temperature lower than the melting point of coenzyme Q 10 .
  • the temperature is not limited to the above-mentioned range and, for example, about 40° C. or above, more preferably about 45° C. or above, can be employed.
  • coenzyme Q 10 dispersed in the form of oil droplets in the above-mentioned poor solvent needs to be solidified at a temperature not higher than the melting point of coenzyme Q 10 , while maintaining the shape of dispersion droplets.
  • the temperature only needs to be set to not more than the melting point of coenzyme Q 10 .
  • the temperature is preferably cooled to 40° C. or below, further to 35° C. or below.
  • the cooling rate is preferably not more than 1.2° C./min, more preferably not more than 1.0° C./min.
  • the cooling rate is preferably not less than 0.01° C./min, more preferably not less than 0.05° C./min.
  • melted coenzyme Q 10 needs to be dispersed in the form of oil droplets and cooled while maintaining the dispersion state.
  • stirring for cooling the dispersion is performed generally at required power per unit volume of not less than 0.01 kW/m 3 , preferably not less than 0.1 kW/m 3 , more preferably not less than 0.3 kW/m 3 , more preferably under flow conditions of not less than 0.5 kW/m 3 .
  • the upper limit of the required power for stirring is not particularly limited, when the required power is markedly high, bubbles from liquid free surface are severely sucked in, causing disorders when coenzyme Q 10 is solidified, such as deformation and the like.
  • the upper limit of the required power for stirring is preferably not more than 1.5 kW/m 3 , more preferably not more than 1.0 kW/m 3 .
  • the above-mentioned stirring is generally performed by rotation of impellers. As long as the above-mentioned flow is achieved, use of an impeller is not necessarily required and, for example, a method utilizing circulation of a liquid and the like can also be considered.
  • the thus-obtained coenzyme Q 10 solid particles are subjected to, for example, solid-liquid separation by centrifugation, filtration by pressurization, filtration under reduced pressure and the like, and further to cake washing as necessary, and a drying treatment by vacuum drying and the like to afford dry particles.
  • the series of operations are preferably performed in deoxygenated atmosphere.
  • the deoxygenated atmosphere can be provided by purging with inert gas, reduced pressure, boiling or a combination thereof.
  • inert gas examples include nitrogen gas, helium gas, argon gas, hydrogen gas and carbon dioxide gas, with preference given to nitrogen gas.
  • easily handlable coenzyme Q 10 particles can be obtained.
  • the size of the obtained coenzyme Q 10 particles can be optionally changed according to the amount and kind the organic solvent or surfactant to be used, the above-mentioned stirring conditions for dispersing coenzyme Q 10 oily substance and the like.
  • coenzyme Q 10 particles obtained by the preferable production method of the present invention are particles having high sphericity and superior in powder flowability characteristics.
  • coenzyme Q 10 particles having Dr. CARR's Flowability Index of not less than 80 can be obtained. From the aspect of powder flowability characteristics, a higher index is more preferable.
  • coenzyme Q 10 particles of not less than 85, further not less than 90 can also be obtained.
  • CARR's Flowability Index is less than 50, as in coenzyme Q 10 bulk powder obtained by a known crystallization method, problems occur in productivity and operability, since flowability is degraded, efficiency during delivery of coenzyme Q 10 particles decreases, an apparatus filling does not proceed smoothly and the like.
  • the Dr. CARR's Flowability Index is an index obtained by total evaluation of angle of repose, compressibility, angle of spatula and uniformity coef. of particles, which is defined in CHEMICAL ENGINEERING-Jan. 18, 1965.
  • the definition relating to the aforementioned powder flowability index is shown in Table 1.
  • the coenzyme Q 10 particles obtained by the preferable production method of the present invention have, for example, depending on the granulation conditions, an angle of repose of 20-45°. Particles having a smaller angle of repose are particles having superior flowability with roundness and free of corners.
  • the coenzyme Q 10 particles obtained by the production method of the present invention have high sphericity, which is, depending on the production conditions, for example, not less than 0.7, more preferably not less than 0.8.
  • the coenzyme Q 10 particles obtained by the preferable production method of the present invention have a spherical or granular shape.
  • the mean particle size thereof is not particularly limited by stirring rate, cooling rate and the like during production, and can be appropriately adjusted.
  • the mean particle size is generally not more than about 3 mm, further preferably not more than about 1 mm. In consideration of use in a mixture with other additives etc., it is particularly preferably not more than about 500 ⁇ m. more preferably not more than about 300 ⁇ m.
  • the mean particle size of the obtained coenzyme Q 10 particles is generally adjusted to not less than about 1 ⁇ m.
  • the mean particle size of the obtained coenzyme Q 10 particles is preferably 50-1000 ⁇ m.
  • the mean particle size is preferably 50-300 ⁇ m.
  • the mean particle size of coenzyme Q 10 particles exceeds 300 ⁇ m, problems occur since, for example, the filling amount during tableting and soft capsule filling is not uniform and the like.
  • excipient and coating agent are not required for granulation.
  • a surfactant or a water-soluble dispersing agent since the amount is extremely small quantity, the obtained coenzyme Q 10 particles show a high coenzyme Q 10 content.
  • the particles have a coenzyme Q 10 content of not less than 90 wt %, more preferably not less than 95 wt %.
  • the obtained coenzyme Q 10 particles have a coenzyme Q 10 content of almost 100 wt %.
  • Particles having a higher coenzyme Q 10 content are preferable, since production efficiency is improved, and the degree of freedom of design during formulation of preparations is high, when used for foods or pharmaceutical products. However, it does not exclude addition or mixing of coenzyme Q 10 particles obtained by the production method of the present invention to or with an excipient or coating thereof as necessary.
  • the coenzyme Q 10 in coenzyme Q 10 particles obtained by the preferable production method of the present invention has, for example, depending on the granulation conditions, crystallinity of not more than 90%, more preferably not more than 50%.
  • crystallinity of not more than 90%, more preferably not more than 50%.
  • coenzyme Q 10 in the particles has a high ratio of amorphous structures. Consequently, the oral absorbability becomes higher as compared to coenzyme Q 10 bulk powder and coenzyme Q 10 processed product having a high crystallinity structure.
  • the coenzyme Q 10 particles obtained by the production method of the present invention can be tableted or filled in a soft capsule as they are, or can be processed in the same manner as with coenzyme Q 10 bulk powder, for example, dissolved in or mixed with fats and oils having affinity and the like, and put to use.
  • the present invention is explained in more detail in the following by referring to Examples.
  • the starting material of coenzyme Q 10 particles used was oxidized coenzyme Q 10 (bulk powder) or reduced coenzyme Q 10 (bulk powder) manufactured by Kaneka Corporation.
  • the coenzyme Q 10 content of the particles used in the Examples was determined by the following HPLC analysis. The content of the obtained coenzyme Q 10 does not define the limit value of the content in the present invention.
  • the crystallinity of coenzyme Q 10 in Examples was evaluated by the following X-RAY analysis apparatus (hereafter to be referred to as XRD).
  • oxidized coenzyme Q 10 particles had an oxidized coenzyme Q 10 content of 99.3 wt %.
  • the obtained oxidized coenzyme Q 10 particles were observed under a microscope (digital microscope VH-6200, manufactured by KEYENCE, hereinafter the same) and found to be granular particles with a mean particle size of about 510 ⁇ m.
  • the obtained oxidized coenzyme Q 10 particles were observed under a scanning electron microscope (S-800, manufactured by Hitachi, Ltd., hereinafter to be referred to as SEM).
  • the sphericity of the obtained coenzyme Q 10 particles was analyzed from the particle photograph taken by SEM and found to be 0.85. Furthermore, the obtained coenzyme Q 10 particles were evaluated by a powder tester (powder tester PT-R type, manufactured by Hosokawa Micron, hereinafter the same) for the powder flowability characteristics. As a result, the angle of repose was 40.4°, Dr. CARR's Flowability Index was 88.5 from other flowability characteristics, and the level of flowability characteristics was “Good”. According to the crystallinity measurement by XRD, the crystallinity of the obtained coenzyme Q 10 particles was 42%.
  • oxidized coenzyme Q 10 particles were obtained.
  • the obtained particles had an oxidized coenzyme Q 10 content of 99.6 wt %.
  • the obtained oxidized coenzyme Q 10 particles were observed under a microscope and found to be granular particles with a mean particle size of about 120 ⁇ m. In addition, the obtained oxidized coenzyme Q 10 particles were observed under SEM.
  • Example 2 Using the same method and the same conditions as in Example 1 except that reduced coenzyme Q 10 (bulk powder, 30 g) and 40 v/v % aqueous ethanol solution (600 mL) were used and all operations were performed under a nitrogen atmosphere, reduced coenzyme Q 10 particles were obtained.
  • the obtained particles had a reduced coenzyme Q 10 content of 99.4 wt %.
  • the obtained reduced coenzyme Q 10 particles were observed under a microscope and found to be granular particles with a mean particle size of about 600 ⁇ m.
  • the obtained reduced coenzyme Q 10 particles were evaluated by a powder tester for the powder flowability characteristics. As a result, the angle of repose was 33.9°, Dr. CARR's Flowability Index was 91.0 from other flowability characteristics, and the level of flowability characteristics was “Excellent”.
  • oxidized coenzyme Q 10 particles were obtained.
  • the obtained particles had an oxidized coenzyme Q 10 content of 99.5 wt %.
  • the obtained oxidized coenzyme Q 10 particles were observed under a microscope and found to be granular particles with a mean particle size of about 370 ⁇ m.
  • the obtained oxidized coenzyme Q 10 particles were evaluated by a powder tester for the powder flowability characteristics. As a result, the angle of repose was 38.5°, Dr. CARR's Flowability Index was 87.5 from other flowability characteristics, and the level of flowability characteristics was “Good”.
  • the oxidized coenzyme Q 10 bulk powder used as the starting material for Examples 1, 2 and 4 was observed under a microscope and found to have been dispersed as a finely divided powder with a mean particle size of about 40 ⁇ m.
  • the oxidized coenzyme Q 10 bulk powder was observed under SEM and, as a result, a finely divided powder substance with low uniformity as shown in FIG. 3 was observed.
  • oxidized coenzyme Q 10 bulk powder was evaluated for the powder flowability characteristics by a powder tester. As a result, the angle of repose was 68.9°, Dr. CARR's Flowability Index was 41.0 from other flowability characteristics, and the level of flowability characteristics was “Poor”.
  • the reduced coenzyme Q 10 bulk powder used as the starting material for Example 3 was observed under a microscope and found to have been dispersed as a finely divided powder with a mean particle size of about 45 ⁇ m.
  • the reduced coenzyme Q 10 bulk powder was evaluated for the powder flowability characteristics by a powder tester. As a result, the angle of repose was 57.7°, Dr. CARR's Flowability Index was 48 from other flowability characteristics, and the level of flowability characteristics was “Poor”.
  • the oxidized coenzyme Q 10 particles obtained by suction filtration and vacuum drying had an oxidized coenzyme Q 10 content of 99.5 wt %.
  • the obtained oxidized coenzyme Q 10 particles were observed under a microscope and found to be spherically-agglomerated crystals with a mean particle size of about 130 ⁇ m.
  • the obtained oxidized coenzyme Q 10 particles were observed under SEM. As a result, an agglomerate of plate crystals as shown in FIG. 4 was observed.
  • the obtained oxidized coenzyme Q 10 particles were evaluated by a powder tester for the powder flowability characteristics. As a result, the angle of repose was 43.7°, Dr. CARR's Flowability Index was 74.5 from other flowability characteristics, and the level of flowability characteristics was “Fair”.
  • Example 4 Comp. Ex. 1 Comp. Ex. 2 Comp. Ex. 3 measurement Found index Found index Found index Found index Found index Found index angle of repose (°) 40.4 17.5 32.9 21 33.9 21 38.5 18 68.9 2.0 57.7 7.0 43.7 16 compressibility (%) 3.5 25 5.2 25 2.3 25 3.9 25 45.2 0.0 40.8 2.0 16.3 19.5 angle of spatula (°) 35 21 35.6 21 37.6 20 39 19.5 56.3 16 51.0 16 59 16 uniformity coef. 1.3 25 1.3 25 1.3 25 1.3 25 1.3 25 1.3 25 1.3 25 1.3 25 1.3 25 1.3 25 1.3 25 1.3 25 1.3 25 1.3 25 1.3 25 1.3 25 1.3 25 1.3 25 1.3 25 1.3 25 2.2 23 2.5 23 2.3 23 total index 88.5 92 91 87.5 41 48 74.5 level of flowability Good Excellent Excellent Good Poor Poor Passable characteristics
  • Ex. 1 Ex. 2 Ex. 3 Ex. 4 Com. Ex. 3 mean particle 510 120 600 370 130 size ( ⁇ m) coenzyme Q 10 99.3 99.6 99.4 99.5 99.5 content (%) sphericity 0.85 1.93 — — — crystallinity (%) 42 32 — — —
  • Oxidized coenzyme Q 10 60 g, bulk powder
  • tetraglycerol monolaurate 0.4 g, manufactured by Sakamoto Yakuhin Kogyo Co., Ltd.: ML-310, HLB 10.3
  • water 1000 g
  • oxidized coenzyme Q 10 was completely melted
  • the mixture was cooled to 20° C. at a cooling rate of 1.0° C./min with stirring (required power for stirring 0.3 kW/m 3 ).
  • the obtained slurry was filtered, and the filtrated particles were washed with water and dried under reduced pressure to give oxidized coenzyme Q 10 particles.
  • the obtained particles generally had a diameter of 100-300 ⁇ m, and showed good flowability and easy handling property.
  • Reduced coenzyme Q 10 60 g, bulk powder
  • tetraglycerol monolaurate 0.4 g, manufactured by Sakamoto Yakuhin Kogyo Co., Ltd.: MO-3S, HLB 8.8 were added to water (1000 g), and the mixture was gradually heated to 60° C. with stirring. After reduced coenzyme Q 10 was completely melted, the mixture was cooled to 20° C. at a cooling rate of 1.0° C./min with stirring (required power for stirring 0.3 kW/m 3 ). All the operations above were performed under a nitrogen atmosphere. The obtained slurry was filtered, and the filtrated particles were washed with water and dried under reduced pressure to give reduced coenzyme Q 10 particles. The obtained particles generally had a diameter of 100-300 ⁇ m, and showed good flowability and easy handling property.
  • Reduced coenzyme Q 10 60 g, bulk powder
  • safflower oil 6 g
  • the mixture was heated to 60° C. and reduced coenzyme Q 10 was completely melted.
  • This was added to water (1000 g) maintained at 60° C., which contained tetraglycerol monolaurate (0.4 g, manufactured by Sakamoto Yakuhin Kogyo Co., Ltd.: ML-500, HLB 13.5).
  • the mixture was cooled to 20° C. at a cooling rate of 1.0° C./min with stirring (required power for stirring 0.3 kW/m 3 ). All the operations above were performed under a nitrogen atmosphere.
  • the obtained slurry was filtered, and the filtrated particles were washed with water and dried under reduced pressure to give reduced coenzyme Q 10 particles.
  • the obtained particles generally had a diameter of 200-300 ⁇ m, and showed good flowability and easy handling property.
  • Reduced coenzyme Q 10 60 g, bulk powder
  • sucrose laurate 0.4 g, manufactured by Mitsubishi Chemical Foods Co., Ltd.: Ryoto sugar ester L-1695, HLB 16
  • water 1000 g
  • the mixture was gradually heated to 60° C. with stirring.
  • the mixture was cooled to 20° C. at a cooling rate of 1.0° C./min with stirring (required power for stirring 0.3 kW/m 3 ). All the operations above were performed under a nitrogen atmosphere.
  • the obtained slurry was filtered, and the filtrated particles were washed with water and dried under reduced pressure to give reduced coenzyme Q 10 particles.
  • the obtained particles generally had a diameter of 100-300 ⁇ m, and showed good flowability and easy handling property.
  • Oxidized coenzyme Q 10 60 g, bulk powder), vitamin E (0.1 g) and hexaglycerol monolaurate (0.4 g, manufactured by Sakamoto Yakuhin Kogyo Co., Ltd.: ML-500, HLB 13.5) were added to water (1000 g), and the mixture was gradually heated to 60° C. with stirring. After oxidized coenzyme Q 10 was completely melted, the mixture was cooled to 20° C. at a cooling rate of 1.0° C./min with stirring (required power for stirring 0.3 kW/m 3 ). The obtained slurry was filtered, and the filtrated particles were washed with water and dried under reduced pressure to give oxidized coenzyme Q 10 particles. The obtained particles generally had a diameter of 50-300 ⁇ m, and showed good flowability and easy handling property.
  • Oxidized coenzyme Q 10 60 g, bulk powder
  • sucrose stearate 0.4 g, manufactured by Mitsubishi Chemical Foods Co., Ltd.: Ryoto sugar ester S-570, HLB 5
  • water 1000 g
  • Oxidized coenzyme Q 10 was completely melted, the mixture was cooled to 20° C. at a cooling rate of 1.0° C./min with stirring (required power for stirring 0.3 kW/m 3 ).
  • Oxidized coenzyme Q 10 mostly adhered to the walls of the container and solidified, and a part thereof formed a large mass with a diameter of about 2 cm.
  • Reduced coenzyme Q 10 60 g, bulk powder
  • tetraglycerolpentaoleic acid ester 0.4 g, manufactured by Sakamoto Yakuhin Kogyo Co., Ltd.: PO-3S, HLB 3
  • water 1000 g
  • reduced coenzyme Q 10 was completely melted
  • the mixture was cooled to 20° C. at a cooling rate of 1.0° C./min with stirring (required power for stirring 0.3 kW/m 3 ). All the operations above were performed under a nitrogen atmosphere.
  • Reduced coenzyme Q 10 mostly adhered to the walls of the container and solidified, and a part thereof formed a large mass with a diameter of about 2 cm.

Landscapes

  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biochemistry (AREA)
  • Toxicology (AREA)
  • Nutrition Science (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US12/522,792 2007-01-11 2008-01-10 Method for producing coenzyme Q10 particle Active 2029-03-11 US8568779B2 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
JP2007003144 2007-01-11
JP2007-003143 2007-01-11
JP2007003143 2007-01-11
JP2007-003144 2007-01-11
PCT/JP2008/050180 WO2008084828A1 (ja) 2007-01-11 2008-01-10 補酵素ｑ10粒子の製造方法

Publications (2)

Publication Number Publication Date
US20100004473A1 US20100004473A1 (en) 2010-01-07
US8568779B2 true US8568779B2 (en) 2013-10-29

Family

ID=39608715

Family Applications (1)

Application Number Title Priority Date Filing Date
US12/522,792 Active 2029-03-11 US8568779B2 (en) 2007-01-11 2008-01-10 Method for producing coenzyme Q10 particle

Country Status (3)

Country Link
US (1) US8568779B2 (ja)
JP (1) JP5292105B2 (ja)
WO (1) WO2008084828A1 (ja)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11471426B2 (en) 2019-10-16 2022-10-18 American River Nutrition, Llc Compositions comprising quinone and/or quinol and methods of preparations and use thereof

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110123505A1 (en) * 2007-08-22 2011-05-26 Kaneka Corporation Method of producing reduced coenzyme q10 and method of stabilizing the same
JPWO2009025372A1 (ja) * 2007-08-23 2010-11-25 株式会社カネカ 還元型補酵素ｑ１０含有組成物及びその安定化方法
NZ595512A (en) 2009-03-31 2013-11-29 Mitsubishi Gas Chemical Co Production method for ubiquinone powder for use in preparations and product thereof
US9655849B2 (en) 2011-03-18 2017-05-23 Particle Dynamics International, Llc Solid particulate compositions comprising coenzyme Q10
EP3053996A4 (en) * 2013-09-30 2017-05-31 Nagase Medicals Co., Ltd. Endoscope lens cleaner
WO2020029017A1 (en) 2018-08-06 2020-02-13 Inner Mongolia Kingdomway Pharmaceutical Co., Ltd. Systems and methods for producing coenzyme q10
US20210361581A1 (en) * 2018-10-22 2021-11-25 Ioi Oleo Gmbh Additive for a powder material intended for compaction into shaped bodies
EP4101442B1 (en) 2021-06-11 2025-09-03 Tradichem Industrial Services, S.L. Process for preparing compacted coenzyme q10 particles of high density and improved flowability
US20250270471A1 (en) * 2022-04-21 2025-08-28 Merck Sharp & Dohme Llc Process for preparing agglomerated crystalline medium-chain fatty acid sodium salts
CN117919195B (zh) * 2024-02-05 2024-07-05 广东润和生物科技有限公司 一种强效抗氧化辅酶q10的制备方法

Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS56103109A (en) 1979-08-31 1981-08-18 Eisai Co Ltd Ubidecarenone-containing composition having improved dispersion properties
US5133979A (en) * 1987-02-26 1992-07-28 Bio Polymers Pty. Ltd. Plant gum material and use thereof in food products
JPH09124405A (ja) 1995-08-18 1997-05-13 Rohm & Haas Co ビーズ状の生成物の製造方法
US6346276B1 (en) * 1997-10-24 2002-02-12 Asahi Kasei Kabushiki Kaisha Composition containing useful substances originating in fishes and shellfishes and process for the preparation of the substances
US20020036154A1 (en) * 2000-08-10 2002-03-28 Ramaswamy Murari Solid pharmaceutical dosage formulation of hydrophobic drugs
WO2003006411A1 (fr) 2001-07-13 2003-01-23 Kaneka Corporation Procede de cristallisation d'une coenzyme q10 reduite a partir d'une solution aqueuse
JP2003089669A (ja) 2001-07-13 2003-03-28 Kanegafuchi Chem Ind Co Ltd 還元型補酵素ｑ１０の結晶化法
US20030104018A1 (en) * 1996-12-31 2003-06-05 Griscom Bettle Skin product having micro-spheres, and processes for the production thereof
US20030228357A1 (en) 2002-02-01 2003-12-11 Pfizer Inc. Dry granulated formulations of azithromycin
JP2004123594A (ja) 2002-10-01 2004-04-22 Asahi Kasei Chemicals Corp ユビデカレノン混合粉体および錠剤の製造方法
US20050074860A1 (en) 2003-09-10 2005-04-07 Takahiro Ueda Reduced coenzyme Q10 crystal with excellent stability and composition containing said reduced coenzyme Q10 crystal
WO2005033054A1 (ja) 2003-09-10 2005-04-14 Kaneka Corporation 安定性に優れた還元型補酵素ｑ１０結晶及び還元型補酵素ｑ１０結晶を含有する組成物
US20050152865A1 (en) * 2001-12-10 2005-07-14 Yumiko Yamamoto Ceramide emulsions
US20060134085A1 (en) * 2003-01-17 2006-06-22 Rumi Yamaguchi Compositions containing coenzyme q10
JP2006213601A (ja) 2005-02-01 2006-08-17 Nof Corp ユビデカレノン含有粉体及びその製造方法

Patent Citations (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS56103109A (en) 1979-08-31 1981-08-18 Eisai Co Ltd Ubidecarenone-containing composition having improved dispersion properties
US5133979A (en) * 1987-02-26 1992-07-28 Bio Polymers Pty. Ltd. Plant gum material and use thereof in food products
JPH09124405A (ja) 1995-08-18 1997-05-13 Rohm & Haas Co ビーズ状の生成物の製造方法
US5688742A (en) 1995-08-18 1997-11-18 Rohm And Haas Company Water based formation of a beaded product
US20030104018A1 (en) * 1996-12-31 2003-06-05 Griscom Bettle Skin product having micro-spheres, and processes for the production thereof
US6346276B1 (en) * 1997-10-24 2002-02-12 Asahi Kasei Kabushiki Kaisha Composition containing useful substances originating in fishes and shellfishes and process for the preparation of the substances
US20020036154A1 (en) * 2000-08-10 2002-03-28 Ramaswamy Murari Solid pharmaceutical dosage formulation of hydrophobic drugs
WO2003006411A1 (fr) 2001-07-13 2003-01-23 Kaneka Corporation Procede de cristallisation d'une coenzyme q10 reduite a partir d'une solution aqueuse
JP2003089669A (ja) 2001-07-13 2003-03-28 Kanegafuchi Chem Ind Co Ltd 還元型補酵素ｑ１０の結晶化法
US20040197886A1 (en) 2001-07-13 2004-10-07 Takahiro Ueda Method of crystallizing reduced coenzyme Q10 from aqueous solution
US20050152865A1 (en) * 2001-12-10 2005-07-14 Yumiko Yamamoto Ceramide emulsions
US20030228357A1 (en) 2002-02-01 2003-12-11 Pfizer Inc. Dry granulated formulations of azithromycin
JP2005526020A (ja) 2002-02-01 2005-09-02 ファイザー・プロダクツ・インク アジスロマイシンの乾式造粒配合物
JP2004123594A (ja) 2002-10-01 2004-04-22 Asahi Kasei Chemicals Corp ユビデカレノン混合粉体および錠剤の製造方法
US20060134085A1 (en) * 2003-01-17 2006-06-22 Rumi Yamaguchi Compositions containing coenzyme q10
US20050074860A1 (en) 2003-09-10 2005-04-07 Takahiro Ueda Reduced coenzyme Q10 crystal with excellent stability and composition containing said reduced coenzyme Q10 crystal
WO2005033054A1 (ja) 2003-09-10 2005-04-14 Kaneka Corporation 安定性に優れた還元型補酵素ｑ１０結晶及び還元型補酵素ｑ１０結晶を含有する組成物
JP2006213601A (ja) 2005-02-01 2006-08-17 Nof Corp ユビデカレノン含有粉体及びその製造方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
F Carli, EE Chiellini, B Bellich, S Macchiavelli, G Cadelli. "Ubidecarenone nanoemulsified composite systems." International Journal of Pharmaceutics, vol. 291, 2005, pp. 113-118. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11471426B2 (en) 2019-10-16 2022-10-18 American River Nutrition, Llc Compositions comprising quinone and/or quinol and methods of preparations and use thereof
US12226374B2 (en) 2019-10-16 2025-02-18 American River Nutrition, Llc Compositions comprising quinone and/or quinol and methods of preparations and use thereof

Also Published As

Publication number Publication date
JPWO2008084828A1 (ja) 2010-05-06
US20100004473A1 (en) 2010-01-07
WO2008084828A1 (ja) 2008-07-17
JP5292105B2 (ja) 2013-09-18

Similar Documents

Publication Publication Date Title
US8568779B2 (en) Method for producing coenzyme Q10 particle
JP5140585B2 (ja) 還元型補酵素ｑ１０含有組成物およびその製造方法
JP5244790B2 (ja) 還元型補酵素ｑ１０含有粒子状組成物及びその製造方法
CN1620413B (zh) 还原型辅酶q10的稳定方法和组合物
EP2098222A1 (en) Physiologically active substance-containing granular composition and method of producing the same
JP5343002B2 (ja) 生理活性物質含有組成物
JP5377304B2 (ja) 補酵素ｑ１０含有組成物
JP5324755B2 (ja) 粒子状組成物およびその製造方法
JP2010515447A (ja) カロテノイドを含有する液体製剤
WO2008029909A1 (fr) Composition comprenant une coenzyme q10 réduite et de la lysolécithine
US20050092969A1 (en) Method of stabilizing compound having quinone skeleton and stabilized composition
US20100168249A1 (en) Composition containing reduced coenzyme q10, and method for stabilizing the composition
JP2009149584A (ja) 還元型補酵素ｑ１０含有粒子状組成物及びその製造方法
US20100092560A1 (en) Reduced coenzyme q10-containing particulate composition and method for producing the same
JPWO2005035477A1 (ja) キノン骨格を有する化合物の安定化方法及び安定化された組成物
JP2009029755A (ja) 補酵素ｑ１０粒子の製造方法
US8388950B2 (en) Coenzyme Q10-containing water-soluble composition and process for production thereof
JP5103188B2 (ja) 酸化に対して安定な還元型補酵素ｑ１０含有組成物、及び還元型補酵素ｑ１０を安定化する方法
JP2007135516A (ja) プロポリス粉体被覆物及びその製造方法、並びにプロポリス含有食品
CN1691935A (zh) 抗坏血酸盐的悬浮液及其作为抗氧化剂的用途
JP2008001669A (ja) 脂溶性還元型補酵素ｑ１０組成物およびその製造方法

Legal Events

Date Code Title Description
AS Assignment

Owner name: KANEKA CORPORATION, JAPAN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:KANAYA, KENTO;KITAMURA, SHIRO;UEDA, TAKAHIRO;REEL/FRAME:022942/0035

Effective date: 20090630

AS Assignment

Owner name: KANEKA CORPORATION, JAPAN

Free format text: CHANGE OF ADDRESS;ASSIGNOR:KANEKA CORPORATION;REEL/FRAME:031207/0283

Effective date: 20130107

STCF Information on status: patent grant

Free format text: PATENTED CASE

CC Certificate of correction
FPAY Fee payment

Year of fee payment: 4

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 8TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1552); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

Year of fee payment: 8

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 12TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1553); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

Year of fee payment: 12